Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept
Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here...
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| Format: | Article |
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MDPI AG
2019-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/11/1330 |
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| author | Tasleem Arif Oriel Stern Srinivas Pittala Vered Chalifa-Caspi Varda Shoshan-Barmatz |
| author_facet | Tasleem Arif Oriel Stern Srinivas Pittala Vered Chalifa-Caspi Varda Shoshan-Barmatz |
| author_sort | Tasleem Arif |
| collection | DOAJ |
| description | Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of reducing hVDAC1 expression in a glioblastoma xenograft using human-specific si-RNA (si-hVDAC1) for a short (19 days) and a long term (40 days). Tumors underwent reprograming, reflected in rewired metabolism, eradication of cancer stem cells (CSCs) and differentiation. Short- and long-term treatments of the tumors with si-hVDAC1 similarly reduced the expression of metabolism-related enzymes, and translocator protein (TSPO) and CSCs markers. In contrast, differentiation into cells expressing astrocyte or neuronal markers was noted only after a long period during which the tumor cells were hVDAC1-depleted. This suggests that tumor cell differentiation is a prolonged process that precedes metabolic reprograming and the “disappearance” of CSCs. Tumor proteomics analysis revealing global changes in the expression levels of proteins associated with signaling, synthesis and degradation of proteins, DNA structure and replication and epigenetic changes, all of which were highly altered after a long period of si-hVDAC1 tumor treatment. The depletion of hVDAC1 greatly reduced the levels of the multifunctional translocator protein TSPO, which is overexpressed in both the mitochondria and the nucleus of the tumor. The results thus show that VDAC1 depletion-mediated cancer cell metabolic reprograming involves a chain of events occurring in a sequential manner leading to a reversal of the unique properties of the tumor, indicative of the interplay between metabolism and oncogenic signaling networks. |
| first_indexed | 2024-03-12T10:40:46Z |
| format | Article |
| id | doaj.art-772f120578e742fe845a8c1f2a0bd4e4 |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T10:40:46Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-772f120578e742fe845a8c1f2a0bd4e42023-09-02T08:10:55ZengMDPI AGCells2073-44092019-10-01811133010.3390/cells8111330cells8111330Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of ConceptTasleem Arif0Oriel Stern1Srinivas Pittala2Vered Chalifa-Caspi3Varda Shoshan-Barmatz4Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelNational Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelReprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of reducing hVDAC1 expression in a glioblastoma xenograft using human-specific si-RNA (si-hVDAC1) for a short (19 days) and a long term (40 days). Tumors underwent reprograming, reflected in rewired metabolism, eradication of cancer stem cells (CSCs) and differentiation. Short- and long-term treatments of the tumors with si-hVDAC1 similarly reduced the expression of metabolism-related enzymes, and translocator protein (TSPO) and CSCs markers. In contrast, differentiation into cells expressing astrocyte or neuronal markers was noted only after a long period during which the tumor cells were hVDAC1-depleted. This suggests that tumor cell differentiation is a prolonged process that precedes metabolic reprograming and the “disappearance” of CSCs. Tumor proteomics analysis revealing global changes in the expression levels of proteins associated with signaling, synthesis and degradation of proteins, DNA structure and replication and epigenetic changes, all of which were highly altered after a long period of si-hVDAC1 tumor treatment. The depletion of hVDAC1 greatly reduced the levels of the multifunctional translocator protein TSPO, which is overexpressed in both the mitochondria and the nucleus of the tumor. The results thus show that VDAC1 depletion-mediated cancer cell metabolic reprograming involves a chain of events occurring in a sequential manner leading to a reversal of the unique properties of the tumor, indicative of the interplay between metabolism and oncogenic signaling networks.https://www.mdpi.com/2073-4409/8/11/1330cancer stem cellsdifferentiationglioblastomamitochondriasi-rnatspovdac1 |
| spellingShingle | Tasleem Arif Oriel Stern Srinivas Pittala Vered Chalifa-Caspi Varda Shoshan-Barmatz Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept Cells cancer stem cells differentiation glioblastoma mitochondria si-rna tspo vdac1 |
| title | Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept |
| title_full | Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept |
| title_fullStr | Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept |
| title_full_unstemmed | Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept |
| title_short | Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept |
| title_sort | rewiring of cancer cell metabolism by mitochondrial vdac1 depletion results in time dependent tumor reprogramming glioblastoma as a proof of concept |
| topic | cancer stem cells differentiation glioblastoma mitochondria si-rna tspo vdac1 |
| url | https://www.mdpi.com/2073-4409/8/11/1330 |
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